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Anti-tumour activity of the cyclotide cycloviolacin O2 on human cancer cell lines in a hollow fibre model
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-93651OAI: oai:DiVA.org:uu-93651DiVA: diva2:167191
Available from: 2005-10-28 Created: 2005-10-28 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Cytotoxic Cyclotides: Structure, Activity, and Mode of Action
Open this publication in new window or tab >>Cytotoxic Cyclotides: Structure, Activity, and Mode of Action
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cyclotides are small cyclic plant proteins, and this thesis addresses their cytotoxic structure-activity properties and their mode of action on human cancer cell lines.

Cyclotides were isolated from Viola odorata and Viola tricolor; three novel cyclotide sequences and two known sequences, but of new origin, were identified using mass spectrometry, amino acid analysis, and Edman degradation. The cyclotide structure includes three disulphide bonds in a knotted arrangement, which forces hydrophobic amino acid residues to be exposed on the surface of the molecule; 3-D homology models of cyclotides have revealed an amphipathic surface and charged residues located at similar positions in the molecules.

The charged amino acid residues were shown to play a key role in the cytotoxicity of the cyclotide cycloviolacinO2 on a human lymphoma cell line. Methylation of Glu caused a dramatic change in cytotoxicity, lowering the potency 48 times, whereas concealing the charge of Arg with 1,2-cyclohexanedione caused virtually no change in potency. Acetylation of the two Lys caused a 3-fold reduction in potency, and masking all positive charges caused a 7-fold reduction. Additionally, disturbing the amphipathic structure by reducing and alkylating the disulphide bonds abolished the cytotoxicity.

The time dependency of cytotoxicity and cell gross morphology after cyclotide exposure were investigated on the lymphoma cell line. Cells exposed to 4 µM of cycloviolacinO2 showed necrotic characteristics, such as membrane disintegration, within 5 min; a membrane disruptive effect of cycloviolacinO2 was also observed in a functional assay based on liposomes at a peptide-to-lipid molar ratio of 6.5.

The anti-tumour properties of cycloviolacinO2 were evaluated on three human cancer cell lines using the hollow fibre assay in vitro and in vivo. The cyclotide exhibited potent anti-tumour activity in the micro-molar concentration range on all cell lines in vitro, but no effect on tumour growth could be established in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 19
Pharmacognosy, cyclotide, cytotoxic, cancer, cyclic cystine knot, Viola, Violaceae, liposome, hollow fibre, homology modelling, mass spectrometry, amphipathic, structure–activity, tumour, membrane disruption, necrosis, Farmakognosi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-6028 (URN)91-554-6378-9 (ISBN)
Public defence
2005-11-18, Room C4:301, BMC, Uppsala, 13:15 (English)
Available from: 2005-10-28 Created: 2005-10-28 Last updated: 2009-10-07Bibliographically approved

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